Lecture 3 – Vaccines.
Part 1
The major physiologic function of the immune system:
Protection against infections
The major physiologic function of the immune system:
Vibrio cholerae Aspergillus fumigatus Listeria monocitogenes Hepatitis B
Protection against infections
Candida albicans Polio virus
HIV Mycobacterium sp.
Categories of pathogenic microorganisms
Extracellular bacteria
Intracellular bacteria
Fungi
Viruses
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Key events during infection – Pathogen point of view
1. entry of the microbe
2. invasion and colonization of host tissues
3. evasion of host immunity
4. tissue injury or functional impairment
Key events during infection – Immune system point of view
1. Innate immunity
2. Adaptive immunity
Detailed immune response against
o Extracellular bacteria
o Intracellular bacteria
o Virus
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
Opsonisation and phagocytosis
Membrane attack complex
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
Opsonisation and phagocytosis
Membrane attack complex
2. Activation of phagocytes and inflammation
Directly: Mannose, Scavenger and Toll-like (TLR) receptors
Indirectly: Fc receptors in opsonised bacteria
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
2. Activation of phagocytes and inflammation
Directly: Mannose, Scavenger and Toll-like (TLR) receptors
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
2. Activation of phagocytes and inflammation
Directly: Mannose, Scavenger and Toll-like (TLR) receptors
Indirectly: Fc receptors in opsonised bacteria
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
Opsonisation and phagocytosis
Membrane attack complex
2. Activation of phagocytes and inflammation
Directly: Mannose, Scavenger and Toll-like (TLR) receptors
Indirectly: Fc receptors in opsonised bacteria
3. Inflammation: leukocyte infiltration into sites of infection
Extracellular bacteria – innate immunity
1. Complement activation via peptidoglycans (G+) and LPS (G-) ->>
2. Activation of phagocytes and inflammation
3. Inflammation: leukocyte infiltration into sites of infection
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – adaptive immunity
1. Humoral immunity
Blocking infection
Elimination of microbes through opsonisation and phagocytosis (IgG1, IgG3)
Neutralisation of toxins (IgG, IgM, IgA (mucosal organs))
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – adaptive immunity
1. Humoral immunity
Blocking infection
Elimination of microbes through opsonisation and phagocytosis (IgG1, IgG3)
Neutralisation of toxins (IgG, IgM, IgA)
2. Activation of CD4+ helper T cells
TH17
TH1
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Extracellular bacteria – Vaccines
Detailed immune response against
o Extracellular bacteria
o Intracellular bacteria
o Virus
Intracellular bacteria – innate immunity
1. Activation of complement?
Credit: Alissa Rothchild
Intracellular bacteria – innate immunity
1. No activation of complement
2. Neutrophils, macrophages and NK cells
Intracellular TLRs and bacterial DNA ->> Type I interferon secretion
Secretion of IL-12 and IL-15 ->> NK cell activation
Intracellular bacteria – innate immunity
1. No activation of complement
2. Neutrophils, macrophages and NK cells
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Intracellular bacteria – innate immunity
1. No activation of complement
2. Neutrophils, macrophages and NK cells
Intracellular TLRs and bacterial DNA ->> Type I interferon secretion
Secretion of IL-12 and IL-15 ->> NK cell activation
Innate immunity contains the infection but usually cannot eradicate it
Intracellular bacteria – adaptive immunity
1. Humoral immunity? Useless
2. T-cell mediated immunity
TH1 CD4+ T cells ->> IFNγ secretion helps to phagolysosome destruction
CD8+ CTLs ->> Kill the infected cells
Intracellular bacteria – adaptive immunity
1. Humoral immunity? Useless
2. T-cell mediated immunity
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Intracellular bacteria – adaptive immunity
1. Humoral immunity? Useless
2. T-cell mediated immunity
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Intracellular bacteria – adaptive immunity
1. Humoral immunity? Useless
2. T-cell mediated immunity
TH1 CD4+ T cells ->> IFNγ secretion helps to phagolysosome destruction
CD8+ CTLs ->> Kill the infected cells
The formation of granulomas surrounding infected cells may cause necrosis and
fibrosis of the tissues responsible of clinical symptoms (bacteria is in a latent stage)
Reactivation will lead in an uncontrolled infection
Individual differences in T cell responses will lead to different clinical outcomes
Mechanisms of immune evasion by bacteria
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Detailed immune response against
o Extracellular bacteria
o Intracellular bacteria
o Virus
Virus – innate immunity
1. Response of infected cells:
Secretion of Type I interferon ->> Recognition of viral RNA and DNA via TLRs
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Virus – innate immunity
1. Response of infected cells:
Secretion of Type I interferon ->> Recognition of viral RNA and DNA via TLRs
NK cell activation ->> Lack of MHC class I molecules on infected cells
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Virus – adaptive immunity
1. Humoral immunity – Antibodies block the entry of the virus in the cells
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Virus – adaptive immunity
1. Humoral immunity – Antibodies block the entry of the virus in the cells
2. T-cell mediated immunity - CTLs
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Virus – adaptive immunity
1. Humoral immunity – Antibodies block the entry of the virus in the cells
2. T-cell mediated immunity – CTLs
Latent infections – Viral DNA persists in the host cell but does not replicate
Sometimes, viruses do not cause the disease but the immune system - Hepatitis B
Mechanisms of immune evasion by virus
Cellular and Molecular Immunology
Abbas, Lichtman, Pillai. 8th Edition
Strategies for vaccine development
Strategies for vaccine development
Strategies for active vaccine development
RNA and DNA
vaccines
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Yellow Fever
Polio
Rabies
Inactivated vaccines Polio
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae
Synthetic vaccines Hepatitis (recombinant proteins)
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Yellow Fever
Polio
Rabies
Inactivated vaccines Polio
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae Vaccines – Part 2
Synthetic vaccines Hepatitis (recombinant proteins)
Dr Martinez-Bravo
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
Vaccines – Part 2
Dr Ljungberg
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Yellow Fever
Polio
Rabies
Inactivated vaccines Polio
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae
Synthetic vaccines Hepatitis (recombinant proteins)
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
Mycobacterium tuberculosis (Mtb)
Mtb kills 1.5 million people/year
One third of worldwide population is infected
Latent infection ->> Granulomas in lungs (CD4+ T cells surrounding infected macrophage)
Guirado E, Schlesinger L.
2013; Frontiers in Immunology
DOI:10.3389/fimmu.2013.00098
Mycobacterium tuberculosis (Mtb)
Live attenuated bacteria
Bacillus Calmette-Guerin (BCG) – Modified Mycobacterium bovis sp. without infective antigens
Protective only against TB meningitis and disseminated TB in children under 5, but not
adult pulmonary TB and it does not stop transmission
BCG does not induce humoral immunity and only partial T-cell response
HIV+ patients, reservoirs for Mtb – Potential bacteria spreaders
Ivanyi I. 2021; Tuberculosis
doi.org/10.1016/j.tube.2020.102021
Mycobacterium tuberculosis (Mtb)
New approaches:
Subunits constructs ->> Fusion of proteins containing both replicating and latent stage
antigens, adjuvants, recombinant formulations and genetically modified
BCG or attenuated Mtb
(Voss G, 2018; Andersen P, 2019; Kauffman SHE, 2020)
Viral vaccines ->> Chimp adenovirus expressing Mtb antigens
(McShane H, 2015; Xing Z, 2019)
Live attenuated bacteria ->> Mtb with gene deletions for certain antigens
(Tameris M, 2019; Spertini F, 2015; Aguilo N, 2016; Arbues A, 2013)
New routes of administration:
Inhalation: Mucosa immunity ->> IgA antibodies and/or primed onsite CD8+ T cells
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Yellow Fever
Polio
Rabies
Inactivated vaccines Polio
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae
Synthetic vaccines Hepatitis (recombinant proteins)
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
Flavivirus – Yellow fever
Live attenuated virus
Flavivirus – Yellow fever
Live attenuated virus
Polio virus – Poliomyelitis
Polio virus – Poliomyelitis
Polio virus – Poliomyelitis
First strategy: Inactivated vaccine
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
First strategy: Inactivated vaccine
Viremia
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
Second strategy: Attenuated vaccine
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
Polio virus – Poliomyelitis
Second strategy: Attenuated vaccine
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
Second strategy: Attenuated vaccine
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
Second strategy: Attenuated vaccine
Prof Vincent Racaniello
Columbia University
Polio virus – Poliomyelitis
Solution? Combined strategy Attenuated + Inactivated vaccine
www.polioeradication.org
1st February 2023
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Polio - OPV
Yellow fever
Rabies
Inactivated vaccines Polio - IPV
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae
Synthetic vaccines Hepatitis (recombinant proteins)
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
Strategies for active vaccine development
Type of vaccine Examples
Live attenuated or killed bacteria Bacillus Calmette-Guerin
Cholera
Live attenuated virus Yellow Fever
Polio
Rabies
Inactivated vaccines Polio
Influenza virus
Subunit (antigen) vaccines Tetanus toxoid
Diphtheria toxoid
Conjugate vaccines Pneumococcus
Haemophillus influenzae Vaccines – Part 2
Synthetic vaccines Hepatitis (recombinant proteins)
Dr Martinez-Bravo
Viral vectors Ebola virus
SARS-CoV-2 (AstraZeneca)
DNA vaccines MERS-CoV
Zika virus
Vaccines – Part 2
Dr Ljungberg
RNA vaccines SARS-CoV-2 (Pfizer, Moderna)
